Human immunodeficiency virus type 1 (HIV-1) infection is characterized as a systemic immunosuppressive disorder caused by the viral-mediated depletion of CD4+ T cells, which develops into the profound immunodeficiency that underlies AIDS. The targeting of CD4+ lymphocytes by HIV-1 is thought to result from expression of cell surface CD4 (Dalgleish et al., Nature 312:763–767 (1984)), the chemokine receptor CXCR4 (Feng et al., Science 272:872–877 (1996)) and (upon activation) CCR5 (Alkhatib et al., Science 272:1955–58 (1996)), which act as receptors for the attachment and entry of HIV-1 (Imlach et al., J. Virol. 75(23):11555–11564 (2001)). HIV infection may also result in a particularly massive reduction in the double-positive CD4+ CD8+ T cell population, possibly due to reduced expression of Bcl-2 and concomitant sensitivity to apoptosis (Guillemard et al., Blood 98(7):2166–2174 (2001)). CD4 and CCR5 are also thought to be responsible for HIV infection of macrophages and macrophage-derived cell types in vivo, although the effect this has on the immune system is unresolved (Guillemard et al., supra). The severe immunodeficiency caused by HIV infection is due not only to the low CD4+ T cell numbers but also to the qualitative dysfunction of the lymphocytes (Bogner et al., Infection 29:32–36 (2001)).
The progression of HIV-1 infection is clearly associated with an increase in the viral load in plasma as well as the progressive depletion of CD4+ T cells. Treatment of HIV-1-infected individuals with potent combinations of anti-retroviral drugs can result in a dramatic decline of the viral load to undetectable HIV-1 RNA levels in the majority of patients (Pakker et al., Nat. Med. 4(2):208–14 (1998)). Apart from controlling viral replication, however, the major goal of these antiviral therapies is to achieve a degree of immune reconstitution. Although increases in CD4+ T cell numbers have been observed, the mechanisms underlying T cell repopulation and restoration of function are still unclear, and complete quantitative or qualitative reconstitution of the immune system may not be achieved or may take a long time to be achieved (Pakker et al., supra). The renewal proceeds slowly, suggesting, in some cases, a severe impairment of T-cell progenitors, depending on the stage of the disease and the age of the patient (Chene et al., J. Virol. 73:7533–7542 (1999)). In many cases, recovery of immune functions to almost normal levels has not been achieved (Plana et al., AIDS 14(13):1921–1933 (2000); Hejdeman et al., AIDS Res. Hum. Retro. 17:277–286 (2001)).
The clinical abnormalities correlated with the presence of HIV infection include immune suppression as well as morphologic and histopathologic changes in intestinal mucosa. Pathologic changes in small intestinal tissues from HIV-infected patients include crypt hyperplasia, villus atrophy, and inflammation. Functional changes have included decreased digestive enzyme activities (Heise et al., Gastroenterology 100(6):1521–1527 (1991); Ullrich et al. Ann Intern Med 111 (1):15–21 (1989)) and intestinal permeability (Keating, J. et al., Gut 37(5):623–629 (1995)), indicative of abnormalities in absorptive epithelial cells. Aberrant mucosal antibody responses and compromised epithelial barrier function may contribute to intestinal disease in HIV infection (Janoff et al., J. Infect. Dis. 170(2):299–307 (1994)).
Gastrointestinal complications commonly seen in HIV-infected patients are nutrient malabsorption, malnutrition, diarrhea and weight loss. These symptoms are associated with a rapid clinical course (Ehrenpreis et al., J. Acquir. Immune Defic. Syndr. 5(10):1047–1050 (1992); Ehrenpreis et al., Am J Clin. Pathol. 97(1):21–28 (1992). With the onset of immunodeficiency, opportunistic enteric pathogens contribute to the severity of intestinal disease (Smith et al., Gastroenterol Clin. North Am. 17(3):587–598 (1988); Kotler, D. P. et al., Ann. Intern. Med. 113(6):444–449 Greenson et al., Ann. Intern. Med. 114(5):366–72 (1991)). However, in many instances, intestinal abnormalities are often detected prior to advanced stages of immunodeficiency and in the absence of detectable enteric pathogens (Gillin et al., Ann. Intern. Med. 102(5):619–622 (1985); Heise et al., supra; Ullrich et al., supra; Kotler et al., supra; Greenson et al., supra; and Miller, A. R. et al., Q J Med. 69(260):1009–1019 (1988). Thus the onset of the intestinal mucosal immune system dysregulation may occur early in infection.
The role of tumor necrosis factor (TNF) in gastrointestinal inflammation in HIV infected individuals is unclear. In SIV-infected rhesus monkeys, expression of TNF is known to be variable throughout the disease course; significant levels were present in intestinal mucosa of 5 of 7 asymptomatic animals, and 6 of 8 terminal animals. It was undetectable in the majority of animals in the acute stage of infection, regardless of viral inoculum. A reciprocal relationship was observed between TNF and IL-10. This suggests that the presence of IL-10 in the intestinal mucosa inhibits TNF production by resident macrophages, as has been described previously in other systems (Fiorentino, et al., J. Immunol. 147(11):3815–3822 (1991); de Waal Malefyt et al., J. Exp. Med. 174(5):1209–1220 (1991)).
TNF is also known to increase HIV replication in various monocyte and T cell model systems (Chene et al., J. Virol. 73(9):7533–7542 (1999); Marshall et al., J. Immunol. 162(10):6016(1999); Heguy et al., Antivir. Chem. Chemother. 9(2):149–155 (1998); Munoz-Fernandez et al., J. Allergy Clin. Immunol. 100:838–845 (1997)). Addition of neutralizing anti-TNF antibodies to primary cultures of HIV-infected human T lymphocytes drastically reduces p24 antigen release and prevents CD4+ cell depletion associated with infection (Munoz-Fernandez et al., supra). Anti-TNF also prevents nuclear factor-kappa B activation, which is involved in the activation of HIV replication. On the other hand recent reports suggest that TNF suppresses HIV replication in freshly infected peripheral blood monocytes and alveolar macrophages (Herbein et al., J. Virol. 70(11):7388–7397 (1996)). Additional studies with a large number of patients will be necessary to evaluate the effect of anti-TNF antibody therapy on disease progression.
As indicated above, significant challenges still remain in the scientific and clinical battle against HIV and AIDS. What is needed are improved compositions and methods capable of accelerating and enhancing the immune reconstitution of infected individuals, and effectively treating gastrointestinal complications resulting from HIV infection.
Relevant Literature
Buelow et al., Transplantation 59:649–654 (1995) and references cited therein. Manolios et al., Nature Medicine 3:84–88 (1997) describes oligopeptides derived by rational design which modulate T cell activity. WO 95/13288 by Clayberger et al. which describes peptides capable of modulating T cell activity. References describing methods for designing compounds by computer using structure activity relationships include Grassy et al., J. of Molecular Graphics 13:356–367 (1995); Haiech et al., J. of Molecular Graphics 13:46–48 (1995); Yasri et al., Protein Engineering 11: 959–976 (1996); Ashton et al., Drug Discovery Today 1:71–78 (1996); and Iyer et al., Curr. Pharm. Des. 8:2217–2229 (2002)